1. Field of Invention
This invention relates to a dosing protocol for the administration of botulinum toxin that maximizes efficacy and specificity while minimizing the likelihood of overdosing and undesirable side effects of botulinum toxin treatment.
2. Background of the Invention
Botulinum toxins, in particular botulinum toxin type A, have been used in the treatment of a number of neuromuscular disorders and conditions involving muscular spasm as well as in cosmetic procedures; for example, strabismus, blepharospasm, spasmodic torticollis (cervical dystonia), oromandibular dystonia and spasmodic dysphonia (laryngeal dystonia). The toxin binds rapidly and strongly to presynaptic cholinergic nerve terminals and inhibits the exocytosis of acetylcholine by decreasing the frequency of acetylcholine release thereby reducing or eliminating the activation of postsynaptic muscles, nerves, or effector tissues. This results in local paralysis and hence relaxation of the muscle afflicted by spasm.
The term botulinum toxin as used herein is a generic term embracing the family of toxins produced by the anaerobic bacterium Clostridium botulinum and, to date, seven immunologically distinct toxins have been identified. These have been given the designations A, B, C, D, E, F and G. For further information concerning the properties of the various botulinum toxins, reference is made to the article by Jankovic & Brin, The New England Journal of Medicine, pp 1186-1194, No 17, 1991 and to the review by Charles L Hatheway, Chapter 1 of the book entitled Botulinum Neurotoxin and Tetanus Toxin Ed. L. L. Simpson, published by Academic Press Inc. of San Diego Calif. 1989, the disclosures in which are incorporated herein by reference.
The neurotoxic component of botulinum toxin has a molecular weight of about 150 kilodaltons and is believed to comprise a short polypeptide chain of about 50 kD which is considered to be responsible for the toxic properties of the toxin, and a larger polypeptide chain of about 100 kD which is believed to be necessary to enable the toxin to penetrate the nerve. The “short” and “long” chains are linked together by means of disulphide bridges.
Intramuscular injections of botulinum toxin A are generally used to balance muscle forces across joints, to diminish or decrease painful spasticity, to decrease deforming forces through selective motor paralysis, to diminish neuropathic and nociceptive pain, to diminish dystonic contractures, to decrease muscle deformation after injury or surgery, and to diminish sweating. The target organelles contain soluble NSF attachment receptor (SNARE) proteins and neurotransmitter-containing vesicles which require these SNARE proteins for fusion of the vesicle to the cell membrane and release of neurotransmitter. Targets include neuromuscular junctions, sweat glands, vascular beds and nociceptors.
Therapeutic use of these toxins represents a somewhat unique pharmacokinetic profile. In order for toxin to produce its desired action, it must not only be delivered to the target tissue, e.g. muscle (usually by direct injection), but it must also bind to terminal portions of nerves innervating the target tissue (i.e. the neuromuscular junction), and be transported across the presynaptic terminal membrane into the intracellular domain where the active molecule is cleaved from the binding portion of the divalent complex. Then the active molecule must bind irreversibly and enzymatically inactivate molecules in the nerve terminal specific for neurochemical transmission. Thus the toxin molecules are not delivered systemically to distribute throughout the body. The ultimate target is not a specific muscle or organ but rather molecules located in specific nerves which innervate the target tissue within an anatomically defined region of the target tissue or muscle. For example, within skeletal muscle fibers, nerves do not uniformly distribute through the muscle but rather the terminals of the nerves are restricted to a certain region of the muscle. In the case of muscle fibers, prior research has shown that different muscles have different numbers of neuromuscular junctions and the total number of these neuromuscular junctions is not dependent on the mass or volume of the muscle or the individual but rather on other factors such as the function of the muscle fibers.
Current recommendations and dosing regimens are empirical and utilize dosage based upon bodyweight in, for example, the management of cerebral palsy and in orthopaedic uses. With specific regard to its use in children, the use of botulinum toxin in the management of cerebral palsy and in orthopaedic usage is based on the size and weight of the growing child, rather than age, to insure safety since overall toxicity data was based upon units per kilogram of body weight in primates. U.S. Pat. No. 6,395,277 issued 28 May 2002 shows a dosing regimen for the treatment of cerebral palsy, noting that dosing should occur “preferably . . . in the region of the neuromuscular junction” according to “the number of muscle groups requiring treatment, the age and size of the patient.” Similar dosing regimens base relative dosages upon the size of muscle.
Historically, dosage recommendations for administration of botulinum toxin has been an imprecise science. Recommendations have been made on the basis of body weight, body surface area, size or volume occupied by a specific muscle, etc. The overreaching goal for each of these therapeutic or cosmetic uses of botulinum toxins is that the toxin be administered in a dosage and volume appropriate to achieving the desired response while remaining localized within the desired specific region of injection. Because the ultimate site of toxin action is nerve junctions within certain regions of the target tissue, over- and under-dosing remains a significant challenge. Administration of too high an absolute dose (total number of toxin molecules relative to the total number of neuromuscular junction targets) or too high a volume of injection might produce adverse reactions related to diffusion of the toxin. Diffusion of the toxin into undesired areas could produce inappropriate paralysis or pathophysiological responses. Too high a dose will produce the desired effect of tissue paralysis but also result in toxin distribution to non targeted tissues thereby causing an unintended loss of physiological function in these regions. Additionally, delivery of supraoptimal toxin doses presents an undesired immunological challenge which may cause reduced effectiveness on subsequent administrations of the toxin. When a large volume of toxin is delivered, it is likely that toxin molecules will diffuse to distant targets resulting in the dilution of the effect of the toxin at the desired target and inappropriately exposing other regions to the toxin. In a large volume dosing scenario, a higher overall dose of toxin would be required at a later time to overcome the dilution effect thus increasing the exposure of other tissues. In these cases where inappropriate doses or volumes are used, not only may patient safety be compromised but the cost of the procedure is increased due to wasted toxin or treatment of unanticipated pharmacological outcomes.
Perhaps the most obvious examples of this inappropriate dosage are delivery of toxin based on body weight to individuals who are at the extremes of weight distribution curves. The toxin acts at the neuromuscular junction and the quantity of the aforementioned junctions does not change proportionately with changes in body mass. Hence, in these cases, individuals with high and low body mass would receive inappropriately high or low doses, respectively.
Various recommendations have demonstrated clinical usefulness but fail to address that 1) the toxin acts at the neuromuscular junction, and 2) the number of neuromuscular junctions varies from muscle to muscle, and 3) the number of neuromuscular junctions tends not to vary as a person ages. Neuromuscular junctions for individual muscles are not directly proportional to muscle mass or volume. Rather, the distribution of neuromuscular junctions varies from muscle to muscle and the number of neuromuscular junctions is affected minimally by age and total body weight. The existing dosage recommendations are clinically efficacious in 50 to 70 percent of patients, namely large toddlers and adolescents, but may underdose infants and small toddlers and overdose heavy children, teenagers, and adults. What is needed are more precise dosing methods to delineate optimal number of units, volume, and injection sites for individual muscles, thereby improving efficacy, minimizing protein antigen load and subsequent antibody formation, and decreasing costs.